Clinical Rounds: Anal sac adenocarcinoma

CASE PRESENTATION

A 9-year-old castrated male miniature schnauzer was referred to The University of Tennessee Veterinary Medical Center (UTVMC) for a postoperative oncology consultation. One month earlier, the dog had undergone resection of a 3-cm perianal mass that was associated with the left anal sac and was firmly adherent to surrounding tissue. Apocrine gland adenocarcinoma had been diagnosed on histologic evaluation, with surgical margins noted to be "clean but close."

On presentation to UTVMC, the dog was bright and alert. A small area of thickening was noted in the region of the excised anal sac on digital rectal examination. No abnormalities were seen on a complete blood count and serum chemistry profile. No evidence of metastatic disease was noted on thoracic or abdominal radiographs; cystic calculi were noted as an incidental finding. Cytologic examination of an aspirate obtained from the perianal surgical site was difficult to interpret because of low cellularity; however, findings were suggestive of apocrine gland adenocarcinoma. Surgical excision with biopsy was recommended. No treatment was provided for the cystic calculi since they were not causing clinical signs.

Treatment

In surgery, the thickened tissue was excised, along with 40% of the anal sphincter and a portion of the rectal wall. The mass was marked with ink and sutures before submission. Histologically, the excised tissue included normal-appearing apocrine glands and a well-demarcated nodule of apocrine gland adenocarcinoma cells that extended close to the deep (cranial) margin.

Postoperative complications included swelling, bruising, constipation, and fecal incontinence. Although anal tone was good, the dog was unable to effectively terminate defecations because of scar tissue in the region. Because feces in the rectum were large in diameter and hard on digital palpation, a warm-water enema was administered six days after surgery. The red rubber catheter was advanced rostral to the rectal sutures to avoid traumatizing the site. Once the impacted feces were removed, the dog defecated normally. The owners declined follow-up radiotherapy; rechecks were recommended with their veterinarian every three months, and these were also declined.

Second presentation

Seventeen months after the second surgery, the dog was presented to the teaching hospital for ribbon-shaped feces and straining to defecate. A left perianal mass (8 x 4.5 x 2.5 cm) and enlarged sublumbar lymph nodes were noted on physical examination. A complete blood count and serum chemistry profile revealed increased total calcium (16.5 mg/dl; reference range = 10 to 11.9 mg/dl) and ionized calcium (2.03 mmol/L; reference range = 1.26 to 1.39 mmol/L) concentrations. Abdominal radiographic and ultrasonographic examinations revealed enlarged sublumbar lymph nodes (Figure 1) and a mass in the liver. Two nodules were noted in the pulmonary parenchyma on thoracic radiographs and fluoroscopy; these were suspected to be metastases.

1. A lateral radiograph of the patient taken 18 months after an initial diagnosis of anal sac adenocarcinoma. Marked sublumbar lymphadenopathy (arrows) and splenic enlargement are noted.

The dog was treated in the hospital with saline diuresis and, once the dog was well-hydrated, with furosemide to decrease serum calcium concentrations. Prednisone was prescribed for continued calcium control, and stool softeners were prescribed to ease defecation. Four days after the dog was released from the hospital, the total serum calcium concentration measured by the referring veterinarian was normal.

At the two-week recheck, the perianal mass had enlarged slightly. Toceranib phosphate (Palladia—Pfizer Animal Health) therapy was initiated, and the mass decreased in size within two weeks. After 28 days of treatment with toceranib, the mass size was stable, and blood calcium concentrations remained normal. The toceranib was continued, and the prednisone was gradually tapered over two weeks and then discontinued. Thirty-one days after toceranib treatment was initiated, the dog developed anorexia, vomiting, and diarrhea. The toceranib was temporarily discontinued, and oral metronidazole was administered, after which the diarrhea resolved. Anorexia and lethargy persisted, however, for seven days, at which time oral famotidine treatment was initiated.

Eleven days after toceranib was discontinued, the dog was reevaluated for persistent lethargy and decreased appetite. The perianal mass and sublumbar lymph nodes had increased in size, and hypercalcemia (total calcium concentration = 17.3 mg/dl, ionized calcium concentration = 2.23 mmol/L) was noted on a serum chemistry profile. Toceranib and prednisone therapy were reinstituted, and the dog was treated with saline diuresis for 16 hours and a single dose of pamidronate (Aredia—Novartis Pharmaceuticals). The dog's appetite and attitude improved after fluid administration. Its calcium concentrations subsequently returned to normal, and the prednisone dose was decreased to once a day.

Follow-up

Over the next two months, the dog had intermittent bouts of lethargy, weakness, vomiting, and poor appetite that gradually increased in frequency and duration and were correlated with the presence of hypercalcemia. Initially, clinical signs resolved with administration of intravenous fluids, furosemide, famotidine, analgesics, and antiemetics; however, the dog eventually failed to respond to supportive treatment, and blood urea nitrogen, creatinine, and phosphorus concentrations became mildly increased. Twenty-three months after the initial surgery and three and a half months after toceranib treatment was initiated, the dog was euthanized at the owners' request.

COMMENTS

Anal sac adenocarcinoma accounts for about 17% of perianal tumors in dogs. Most affected dogs are older (average age, 10 to 11 years), and some, though not all, studies report a predisposition in females.1-4 Clinical signs may include tenesmus or perineal swelling, although the mass may be an incidental finding in one-third of animals.1-4 A diagnosis of anal sac adenocarcinoma is suspected based on a palpable thickening of the anal sac or a mass in that region, particularly in dogs with hypercalcemia or sublumbar lymph node enlargement. Definitive diagnosis is based on cytologic examination of an aspirate or histologic examination of a biopsy sample.

Medical perspective

Amy Holford, VMD, DACVIM

Paraneoplastic syndrome with resultant hypercalcemia and hyperphosphatemia is noted in 25% to 50% of dogs with anal sac adenocarcinoma.1-4 Dogs with hypercalcemia may not exhibit any clinical signs or may exhibit polyuria, polydipsia, muscular weakness, vomiting, and constipation. Animals with hypercalcemia of malignancy associated with anal sac adenocarcinoma have a decreased parathyroid hormone (PTH) concentration and an increased PTH-related protein concentration.5 In contrast, dogs with primary hyperparathyroidism have no measureable PTH-related protein concentration and normal or increased PTH concentration in the face of an increased ionized calcium concentration.

Amy Holford, VMD, DACVIM

Besides the clinical signs listed above, hypercalcemia may also result in renal failure from metastatic mineralization, particularly if the calcium-phosphorus product is > 60 to 80.5 Mild hypercalcemia with no evidence of renal failure does not require aggressive therapy if the patient is able to maintain adequate hydration. Acute treatment of marked hypercalcemia includes rehydration if the patient is dehydrated and subsequent saline diuresis at two to three times maintenance fluid rates.5

Once dogs are well-hydrated and volume-expanded, furosemide is administered (5 mg/kg initial intravenous bolus, followed by 2 to 4 mg/kg every eight to 12 hours orally, intravenously, or subcutaneously) during diuresis to promote calcium excretion in the urine. Diuresis and furosemide treatments may be continued until the calcium-phosphorus product decreases to < 60. Electrolytes and magnesium concentrations should be monitored, and supplementation should be provided when necessary. Additional treatments include corticosteroids and bisphosphonates such as pamidronate. Corticosteroids decrease bone resorption and intestinal absorption of calcium and promote renal calcium excretion. Dogs are commonly treated with prednisone or prednisolone (1 to 2 mg/kg orally b.i.d.), and gastroprotectants may be administered concurrently.5 Bisphosphonates inhibit osteoclastic activity and, therefore, bone resorption. In dogs with decreased renal function, the toxicity of bisphosphonates can be minimized by administering them as a two-hour infusion rather than a one-time injection. The infusion can be repeated in one to four weeks if the patient is still hypercalcemic.

During treatment of severe hypercalcemia, hydration should be frequently assessed by physical examination (body weight, skin turgor, mucous membrane wetness) and, in critical patients, by measurement of central venous pressures. Use of diuretics or bisphosphonates in a patient that is dehydrated or has renal compromise can be extremely dangerous, potentially resulting in renal failure or exacerbation of already present renal disease.

Radiology perspective

Alyce Marks, DVM

Initial diagnostic imaging of dogs with suspected anal sac adenocarcinoma should include abdominal radiography, abdominal ultrasonography, and three-view thoracic radiography. Thoracic radiography is still considered the first screening test for pulmonary metastatic disease, and fluoroscopic evaluation may help verify that nodules are within lung parenchyma. Computed tomography has higher sensitivity in the detection of pulmonary nodules, however, and should be considered in patients with questionable lesions on survey radiographs.

Alyce Marks, DVM

Moderate to severe sublumbar lymph node enlargement will be detectable as a sublumbar mass on abdominal radiographs. Mild lymph node enlargement and metastases to the liver or spleen may go undetected on survey radiographs, however, so abdominal ultrasonography should be performed for complete staging. Because ultrasonography does not permit differentiation between subcategories of malignancy and between reactive lymphadenopathy and metastatic neoplasia, ultrasound-guided tissue sampling should be performed to obtain a cytologic or histopathologic diagnosis.6

Clinical pathology perspective

Carolyn Grimes, DVM

Carolyn Grimes, DVM

Cytologic samples of anal sac adenocarcinoma are typically highly cellular and consist of dense, often papillary, cell clusters.7 Cells are fragile, and samples often contain many free nuclei (i.e. "naked nuclei") from disrupted cells. Intact cells are round to polygonal with a small amount of lightly basophilic cytoplasm; they are often observed in short rows and, occasionally, acinar-like arrangements (Figure 2). Cells often appear quite uniform, although some tumors may have more striking features of malignancy. Metastatic lesions (most commonly iliac lymph nodes) appear similar cytologically and are often identified before the primary lesion.7 The typical cytomorphology of this tumor is different from that of perianal gland (hepatoid) adenoma; however, distinguishing between the two tumor types reliably with cytology requires some experience.

2. Cytologic examination of a fine-needle aspirate of an anal sac apocrine gland adenocarcinoma reveals dense papillary cell clusters with abundant, scattered free nuclei. Intact cells are round to polygonal and are occasionally observed in an acinar-like arrangement (inset) (Wright’s stain; background, 200X; inset, 1,000X).

Anatomic pathology perspective

Amanda J. Crews, DVM

Grossly, anal sac adenocarcinoma is usually unilateral, ventrolateral to the anus, in close association with the anal sac, and not attached to the overlying epidermis. Ulceration is rare. Growth is frequently inward toward the pelvic canal. Mass removal should include the entire anal sac. All cut surfaces of the mass and associated tissue should be painted with surgical marking ink before fixation if margin evaluation is desired. On cut section, the mass is typically tan and multilobulated. Neoplastic cells are often surrounded by a fibroblastic response (desmoplasia), which makes the tumor firm on palpation.

Amanda J. Crews, DVM

Histologically, anal sac adenocarcinoma can be readily differentiated from other perianal tumors, such as anal sac adenoma, perianal (hepatoid) gland adenoma, perianal gland epithelioma, perianal gland adenocarcinoma, and sebaceous tumors. Anal sac adenocarcinoma cells form in three distinct patterns: solid, rosette, and tubular. Frequently, a combination of all three patterns is present in an individual tumor (Figures 3A & 3B). Similar tumor cell morphology and patterns have been reported in tumors from other parts of the body, so location must be provided to the pathologist to ensure accurate interpretation and diagnosis. Metastatic tumor cells resemble those of the primary tumor but cannot be reliably differentiated from other types of carcinoma cells, particularly endocrine and neuroendocrine, without information about primary tumor location.

3A & 3B. The histologic appearance of anal sac adenocarcinoma. Figure 3A shows a rosette pattern. Figure 3B shows solid, rosette, and tubular patterns in the same tumor (hematoxylin-eosin stain; 40X).

Surgical perspective

Karen M. Tobias, DVM, MS, DACVS

Karen M. Tobias, DVM, MS, DACVS

Mass resection, including the entire anal sac, is the treatment of choice for anal sac adenocarcinoma. It is not necessary to remove the other anal sac if it is unaffected.

4A. A preoperative view of a large anal sac adenocarcinoma in a mixed-breed male dog.

With large masses, a portion of the anus will be included in the resection; in some dogs, a small amount of rectum must also be excised (Figures 4A & 4B). Potential complications of surgery include infection, dehiscence, incontinence, tenesmus, rectocutaneous fistula, and recurrence.1,3 Concurrent removal of infiltrated sublumbar lymph nodes is controversial; improved prognosis was correlated with lymph node resection in one study2 of 80 dogs but not in another study3 of 32 dogs. Potential complications of lymph node removal include severe hemorrhage, urinary incontinence, and death. Postoperative monitoring should include physical and digital rectal examinations, thoracic radiography, and abdominal ultrasonography at one, two, three, and six months after surgery. If recurrence or metastases are not noted by six months after surgery, rechecks are often extended to twice yearly.

4B. An intraoperative view of the same dog as in Figure 4A. Masses of this size require resection of the anal sphincter and a portion of the rectal wall.

Medical oncology perspective

Olya Smrkovski, DVM, DACVIM (oncology)

Anal sac adenocarcinoma is an aggressive neoplasm, with metastatic disease reported in more than 50% of dogs at the time of diagnosis.1-4 The most common site of metastasis is the sublumbar lymph nodes, but the tumor may also spread to the lungs, liver, spleen, and bone. The underlying etiology of the tumor is unknown, although breed predisposition has been reported in cocker spaniels.1,2

Olya Smrkovski, DVM, DACVIM (oncology)

Negative prognostic indicators include the presence of metastases, a primary tumor size > 10 cm2, and a lack of surgical therapy. In one study, hypercalcemia at the time of diagnosis was also associated with shorter median survival time.4 With treatment, survival of dogs with small masses (< 2.5 cm) and no lymph node enlargement or metastatic disease is more than three years.2 Dogs with larger masses but no lymph node enlargement have a median survival time of about two years, and dogs with enlarged lymph nodes have a median survival time of one to one and a half years.2 If evidence of pulmonary metastasis is found, the median survival time decreases to 219 days.

While surgery is the most appropriate treatment for dogs with no metastasis on presentation, a multimodal approach, including radiation therapy and chemotherapy, is likely beneficial for dogs with nodal metastasis.8 The role of chemotherapy in prolonging the overall survival time of dogs with anal sac adenocarcinoma remains undefined. Doxorubicin, mitoxantrone, and platinum agents have documented antitumor activity and should be considered, especially when surgery and radiation are not options. The median survival time of dogs treated with chemotherapy alone is 212 days.4 The effectiveness of toceranib for treating anal sac adenocarcinoma has not been reported; however, short-term resolution of hypercalcemia and reduction in local recurrence and metastasis of anal sac adenocarcinoma have been noted anectdotally.9 Toceranib's mechanism of action against anal sac adenocarcinomas has not been elucidated.

Radiation oncology perspective

Nathan Lee, DVM, DACVR (radiation oncology)

Local recurrence is seen in 20% to 50% of dogs with anal sac adenocarcinomas treated with surgery alone,1-4 so postoperative definitive radiation therapy should be considered in any patient with a primary tumor > 2.5 cm in diameter. There is no standard of care for radiation therapy of anal sac adenocarcinoma. At The University of Tennessee, our current definitive radiation protocol consists of daily treatments, Monday through Friday, for a total of 24 treatments.

Nathan Lee, DVM, DACVR (radiation oncology)

With definitive radiation therapy, acute side effects to the tissues in the radiation field begin to develop during the third week of treatment and typically consist of moist desquamation and mucositis in the perianal area, colitis, tenesmus, and perineal discomfort. While these effects can appear severe and require proper client education for management, they are self-limiting and usually resolve within 10 to 20 days after radiation therapy is complete.

Late side effects associated with perianal and pelvic radiation are usually seen six months to several years after therapy and may include chronic colitis, rectal or colonic strictures, rectal perforation, pelvic limb edema, secondary tumor formation, and perineal pain. The incidence of late effects is significantly reduced if fraction sizes are reduced to < 2.7 Gy and the total dose is limited to 54 Gy.10,11

Patients with large primary anal sac adenocarcinomas with or without metastasis to the sublumbar lymph nodes may respond to palliative radiation. I have seen dogs receiving a dose of radiation once a week for three to four treatments show a significant decrease in tumor burden, and their quality of life is improved life for about one to one and a half years. It should be stressed, though, that palliative radiation therapy should only be used in patients with marked bulky disease. Palliative radiation therapy using large doses per fraction also significantly increases the risk for late side effects from radiation therapy.10,11

The Clinical Rounds team is from the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996.

REFERENCES

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2. Polton GA, Brearley MJ. Clinical stage, therapy, and prognosis in canine anal sac gland carcinoma. J Vet Intern Med 2007;21(2):274-280.

3. Ross JT, Scavelli TD, Matthiesen DT, et al. Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases. J Am Anim Hosp Assoc 1991;27:349-355.

4. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223(6):825-831.

5. Feldman EC, Nelson RW. Hypercalcemia and primary hyperparathyroidism. Canine and feline endocrinology and reproduction. 3rd ed. Philadelphia, Pa: W.B. Saunders Company, 2003;661-715.

6. Llabrés-díaz F. Ultrasonography of the medial iliac lymph nodes in the dog. Vet Radiol Ultrasound 2004;45(2):156-165.

7. Raskin RE. Skin and subcutaneous tissues. In: Raskin RE, Meyer DJ, eds. Canine and feline cytology: a color atlas and interpretation guide. 2nd ed. St. Louis. Mo: Saunders Elsevier, 2010;26-76.

8. Turek MM, Forrest LJ, Adams WM, et al. Postoperative radiotherapy and mitoxantrone for anal sac adenocarcinoma in the dog: 15 cases (1991-2001). Vet Comp Oncol 2003;1(2):94-104.

9. Brown RJ, Newman SJ, Durtschi DC, et al. Expression of PDGFR-Beta and Kit in canine anal sac apocrine gland adenocarcinoma using tissue immunohistochemistry. Vet Comp Oncol Online publication: 3 Aug 2011.

10. Anderson CR, McNiel EA, Gillette EL, et al. Late complications of pelvic irradiation in 16 dogs. Vet Radiol Ultrasound 2002;43(2):187-192.

11. Arthur JJ, Kleiter MM, Thrall DE, et al. Characterization of normal tissue complications in 51 dogs undergoing definitive radiation irradiation. Vet Radiol Ultrasound 2008;49(1):85-89.